Nature's way to construct highly complex molecular entities with virtue as part of biosynthetic pathways is unmatched by any chemical synthesis. Yet, relying on a cascade of native enzymatic transformations to achieve a certain target structure, biosynthesis is also significantly limited in its scope. In this work, non-natural biocatalytic modules are successfully implemented into an artificial metabolism, combining the benefits of traditional retrosynthesis with the elegance and efficacy of biosynthetic networks. In a highly streamlined process, a total synthesis of the tricyclic angiopterlactone B is achieved operating entirely in an aqueous environment while relying on enzymes as reaction mediators.